Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.
It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery
Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S. Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm., 195: 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.
Two structurally related endothelin receptors have been cloned, sequenced and characterized (Hosada, K.; Nakao, K.; Arai, H.; Suga, S.; Ogawa, Y.; Mukoyama, M.; Shirakami, G.; Saito, Y.; Nakanishi, S.; Imura, H. FEBS Left. 1991, 187, 23-26: Sakamoto, A.; Yanagisawa, M.; Sakurai, T.; Takuwa, Y.; Yanagisawa, H.; Masaki, T. Biochem. Biophys. Res. Commun. 1991,178, 656-663). Each binds the three endothelin isopeptides with differing affinities; the ET.sub.A receptor displays affinity for ET-1 and ET-2 over ET-3, while the ET.sub.B receptor is non-isopeptide selective. Originally described as a vasodilatory receptor due to its mediation of nitric oxide release (DeNucci,G.; Thomas, R.; D'Orleans-Juste, P.; Antunes, E.; Walder, C.; Warner, T. D.; Vane, J. R. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9797-9800), it is now apparent that the ET.sub.B receptor is responsible for a greater diversity of physiologic function. Current research suggests a role for ET.sub.B mediated responses in certain disease states including established pulmonary hypertension (McCulloch, K. M.; MacLean, M. R.; J. Cardiovasc. Pharmacol. 1995, 26(Suppl. 3), S169-S176), contractile dysfunction associated with benign prostatic hyperplasia (Webb, M. L.; Chao, C.-C.; Rizzo, M.; Shapiro, R. A.; Neubauer, M.; Liu, E. C. K.; Aversa, C. R.; Brittain, R. J.; Treiger, B. Mol. Pharmacol. 1995, 47, 730-737; Webb, M. L.; Meek, T. D. Med. Res. Rev. 1997,17,17-67), myocardial infarction (Vitola, J. V.; Forman, M. B.; Holsinger, J. P.; Kawana, M.; Atkinson, J. B.;
Quertermous, T.; Jackson, E. K.; Murray, J. J. J. Cardiovasc. Pharmacol. 1996, 28, 774-783), and atherosclerosis (Dagassan, P. H.; Breu, V.; Clozel, M.; Kunzli, A.; Vogt, P, Turina, M.; Kiowski, Clozel, J. -P. J. Cardiovasc. Pharmacol. 1996, 27, 147-153). Our group has previously reported the discovery of a series of pyrrolidine-3-carboxylic acids which which bind potently and selectively to the ETA receptor subtype (Winn, M.; von Geldern, T. W.; Opgenorth, T. J.; Jae, H. -S.; Tasker, A. S.; Boyd, S. A.; Kester, J. A.; Mantei, R. A.; Bal, R. B.; Sorensen, B. K.; Wu-Wong, J. R.; Chiou, W. J.; Dixon, D. B.; Novosad, E. I.; Hernandez, L.; Marsh, K. C. J. Med. Chem. 1996, 39,1039-1048). The compounds claimed in the current invention differ from those previously described and are unique in that they bind potently and selectively to the ET.sub.B subtype, blocking the actions of the endothelins on these receptors. As such, they may find utility in the treatment of diseases that are mediated by the ET.sub.B receptor.